Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the present invention relates to a method for producing a pyrrolopyrimidine ring-containing tricyclic compound, and to a tricyclic compound capable of being obtained by this production method.
• Non-patent Literature (NPL) 3 and Non-patent Literature (NPL) 4 A pyrrolopyrimidine ring is known as a partial structure commonly possessed by many kinase inhibitors (Non-patent Literature (NPL) 3 and Non-patent Literature (NPL) 4).
• Patent Literature (PTL) 1 has been known as a method for producing a pyrrolopyrimidine ring-containing tricyclic compound.
• an organic borane reagent is caused to act on a pyrrolopyrimidine derivative to prepare an alkyl borane intermediate in the system, and an intramolecular cyclization reaction is then performed using a divalent palladium catalyst to thereby produce a pyrrolopyrimidine ring-containing tricyclic compound.
• this method suffers from low yield, as shown in Comparative Example 1 below.
• Non-patent Literature (NPL) 1 and Non-patent Literature (NPL) 2 The intramolecular cyclization reaction using a zerovalent palladium catalyst has also been known (Non-patent Literature (NPL) 1 and Non-patent Literature (NPL) 2).
• NPL 1 reports a method that uses a zerovalent palladium catalyst and cesium carbonate as a base. However, this method also suffers from low yield, as shown in Comparative Example 2 below.
• NPL 2 reports a method that uses a zerovalent palladium catalyst and thallium carbonate as a base.
• thallium carbonate is an acute toxic substance and is not preferably used in a production method.
• An object of the present invention is to provide a method for reproducibly producing a pyrrolopyrimidine ring-containing tricyclic compound in high yield with reduced formation of by-products, and to provide a novel tricyclic compound.
• the present inventors conducted extensive research to achieve the above object, and found that a combined use of a zerovalent palladium catalyst and an alkali metal hydroxide enables the production of a pyrrolopyrimidine ring-containing tricyclic compound in high yield with high reproducibility, with reduced formation of by-products.
• the present invention has thereby been accomplished.
• the present invention provides the following method for producing a tricyclic compound, and the following tricyclic compound useful as a production intermediate of medicinal drugs and the like.
• the production method of the present invention reproducibly produces a pyrrolopyrimidine ring-containing tricyclic compound in high yield with reduced formation of by-products, and is thus suitable for industrial production.
• the tricyclic compound produced by the production method of the present invention is very useful as a production intermediate of medicinal drugs and the like.
• the present invention provides a method for producing a compound represented by Formula (1) above or a salt thereof, the method comprising the steps of:
• m in the formulae represents an integer of 0 to 2, and is preferably 0 or 1.
• n in the formulae represents an integer that satisfies 0 ⁇ m + n ⁇ 3, and is preferably 1 or 2.
• the functional group represented by R 1 may be any group as long as the production method of the present invention proceeds.
• Specific examples include halogen, hydroxyl, cyano, nitro, alkyl which may be substituted, haloalkyl which may be substituted, cycloalkyl which may be substituted, cycloalkyl-alkyl which may be substituted, aralkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, alkoxy which may be substituted, haloalkoxy which may be substituted, cycloalkoxy which may be substituted, cycloalkyl-alkoxy which may be substituted, aralkyloxy which may be substituted, alkylthio which may be substituted, cycloalkyl-alkylthio which may be substituted, amino which may be substituted, alkylamino which may be substituted, cycloalkyl-alkylamino which may be substituted, acyl
• the functional group represented by R 1 also includes the groups listed above that are protected by protecting groups.
• protecting groups are not limited insofar as they can protect the groups mentioned above. Examples of usable protecting groups include those listed below as protecting groups for protected hydroxyl, protected amino, protected C 1-6 alkylamino, and protected thiol.
• halogen as used herein include fluorine, chlorine, bromine, iodine, and the like, unless otherwise defined.
• Alkyl as used herein may be straight chain or branched chain, and may be, for example, C 1-6 alkyl.
• C 1-6 alkyl refers to C 1-6 straight or branched alkyl, such as methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec- butyl, tert -butyl, n -pentyl, isopentyl, and hexyl, unless otherwise defined.
• Haloalkyl refers to a group in which from one to all of the hydrogen atoms in the alkyl mentioned above are replaced by the halogen mentioned above. Examples include a group in which from one to all of the hydrogen atoms of the C 1-6 alkyl mentioned above are replaced by the halogen mentioned above (C 1-6 haloalkyl).
• C 1-6 haloalkyl examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 3-chloropropyl, 4-chlorobutyl, 5-fluoropentyl, 6-fluorohexyl, and the like.
• C 1-4 haloalkyl such as monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, 1,1,1-trifluoroethyl, monofluoro- n -propyl, perfluoro- n -propyl, perfluoroisopropyl, 3-chloropropyl, and 4-fluorobutyl.
• Cycloalkyl as used herein refers to monocyclic or polycyclic alkyl, such as C 3-10 cycloalkyl.
• C 3-10 cycloalkyl refers to C 3-10 monocyclic or polycyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and decalyl, unless otherwise defined.
• C 3-7 cycloalkyl refers to C 3-7 monocyclic or polycyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, unless otherwise defined.
• cycloalkyl-alkyl examples include C 1-4 alkyl substituted with C 3-7 cycloalkyl, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl.
• aralkyl examples include C 7-13 aralkyl, such as benzyl, phenethyl, naphthylmethyl, and fluorenylmethyl.
• Alkenyl as used herein may be straight, branched, or cyclic, and refers to an unsaturated hydrocarbon group having at least one double bond. Examples include C 2-6 alkenyl, such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2-, or 3-butenyl, 2-, 3-, or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohexenyl, and 3-methyl-3-butenyl; and the like.
• C 2-6 alkenyl such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2-, or 3-butenyl, 2-, 3-, or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohex
• Alkynyl as used herein may be straight, branched, or cyclic, and refers to an unsaturated hydrocarbon group having at least one triple bond. Examples include C 2-6 alkynyl, such as ethynyl, 1- or 2-propynyl, 1-, 2-, or 3-butynyl, and 1-methyl-2-propynyl; and the like.
• Alkoxy as used herein may be straight or branched alkoxy. Examples include C 1-6 alkoxy. C 1-6 alkoxy refers to C 1-6 straight or branched alkoxy, such as methoxy, ethoxy, n -propoxy, isopropoxy, n -butoxy, isobutoxy, tert -butoxy, pentyloxy, isopentyloxy, and hexyloxy, unless otherwise defined.
• Haloalkoxy refers to C 1-6 straight or branched alkoxy containing 1 to 13 halogen atoms ("halo C 1-6 alkoxy"), and preferably halo C 1-4 alkoxy.
• Examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 2,2,2-trifluoroethoxy, monofluoro- n -propoxy, perfluoro- n -propoxy, perfluoro-isopropoxy, 5-fluoropentyloxy, 6-fluorohexyloxy, and the like.
• cycloalkoxy examples include C 3-7 cycloalkoxy, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy; and the like.
• cycloalkyl-alkoxy examples include C 1-4 alkoxy substituted with C 3-7 cycloalkyl, such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, and cycloheptylmethoxy; and the like.
• aralkyloxy examples include C 7-13 aralkyloxy, such as benzyloxy, phenethyloxy, naphthylmethyloxy, and fluorenylmethyloxy; and the like.
• Alkylthio as used herein may be straight or branched. Examples thereof include C 1-6 alkylthio, such as methylthio, ethylthio, n -propylthio, isopropylthio, n -butylthio, isobutylthio, tert- butylthio, n -pentylthio, isopentylthio, hexylthio; and the like.
• cycloalkyl-alkylthio examples include C 1-4 alkylthio substituted with C 3-7 cycloalkyl, such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, and cycloheptylmethylthio; and the like.
• alkylamino examples include a group in which one or two of the hydrogen atoms of amino are replaced by the alkyl mentioned above (“monoalkylamino" or “dialkylamino”).
• C 1-6 alkylamino refers to amino in which one or two of the hydrogen atoms are replaced by the C 1-6 alkyl mentioned above.
• monoalkylamino examples include amino monosubstituted with straight or branched C 1-6 alkyl, such as methylamino, ethylamino, n -propylamino, isopropylamino, n- butylamino, isobutylamino, tert -butylamino, n -pentylamino, isopentylamino, and hexylamino; and the like.
• dialkylamino examples include amino disubstituted with straight or branched C 1-6 alkyl, such as dimethylamino, diethylamino, di- n -propylamino, diisopropylamino, di- n -butylamino, isobutylamino, di- tert -butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, and ethylmethylamino; and the like.
• cycloalkyl-alkylamino examples include C 1-4 alkylamino substituted with C 3-7 cycloalkyl, such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, and cycloheptylmethylamino; and the like.
• Acyl as used herein is a residue obtained by removing hydroxyl from the carboxyl group of a carboxy-containing compound, and indicates alkylcarbonyl or arylcarbonyl.
• alkylcarbonyl examples include straight or branched (C 1-6 alkyl) carbonyl, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n -butylcarbonyl, isobutylcarbonyl, tert -butylcarbonyl, n -pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl; and the like.
• arylcarbonyl examples include (C 6-13 aryl) carbonyl, such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, indanylcarbonyl, and phenanthrylcarbonyl; and the like.
• Acyloxy as used herein refers to alkylcarbonyloxy or arylcarbonyloxy.
• alkylcarbonyloxy examples include straight or branched (C 1-6 alkyl) carbonyloxy, such as methylcarbonyloxy, ethylcarbonyloxy, n -propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert -butylcarbonyloxy, n- pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy; and the like.
• C 1-6 alkyl carbonyloxy such as methylcarbonyloxy, ethylcarbonyloxy, n -propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert -butylcarbonyloxy, n- pentylcarbonyloxy, isopentylcarbonyloxy, and hexyl
• arylcarbonyloxy examples include (C 6-13 aryl) carbonyloxy, such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy; and the like.
• Alkoxycarbonyl refers to carbonyl to which the alkoxy mentioned above is attached, and may be straight or branched. Examples thereof include C 2-7 alkoxycarbonyl. Examples of C 2-7 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n -propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, and the like.
• aralkyloxycarbonyl examples include (C 7-13 aralkyl)oxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, and fluorenylmethyloxycarbonyl; and the like.
• Saturated heterocycle refers to 4- to 10-membered monocyclic or polycyclic, partially saturated or saturated heterocycle having 1 to 4 atoms selected from among oxygen, nitrogen, and sulfur, unless otherwise defined ("4- to 10-membered saturated heterocycle").
• saturated heterocycle include pyrrolidinyl, piperidinyl, piperazinyl, hexamethyleneimino, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
• Examples of partially saturated heterocycle include methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, oxetanyl, and the like. These are preferably monocyclic or bicyclic.
• Unsaturated heterocycle refers to 4- to 10-membered monocyclic or polycyclic unsaturated heterocycle having 1 to 4 atoms selected from among oxygen, nitrogen, and sulfur ("4- to 10-membered unsaturated heterocycle"), unless otherwise defined.
• Specific examples include imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, and the like. These are preferably monocyclic or bicyclic.
• aromatic hydrocarbon examples include phenyl, tolyl, xylyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, tetrahydronaphthyl, and the like. It is preferable to use C 6-14 monocyclic or polycyclic aromatic hydrocarbon ("C 6-14 aromatic hydrocarbon").
• C 6-14 aromatic hydrocarbon examples include phenyl, tolyl, xylyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, tetrahydronaphthyl, and the like. These are preferably monocyclic or bicyclic.
• Saturated heterocyclic oxy refers to oxy to which the saturated heterocycle mentioned above are attached.
• Examples include morpholinyloxy, 1-pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, thiazolidinyloxy, oxazolidinyloxy, and the like.
• the "functional group” represented by R 1 is preferably C 1-6 alkyl which may be substituted, C 3-10 cycloalkyl which may be substituted, C 6-14 aromatic hydrocarbon which may be substituted, 4- to 10-membered saturated heterocycle which may be substituted, or 4- to 10-membered unsaturated heterocycle which may be substituted.
• the "functional group” represented by R 1 may also be a functional group other than C 1-6 alkyl which may be substituted, C 3-10 cycloalkyl which may be substituted, C 6-14 aromatic hydrocarbon which may be substituted, 4- to 10-membered saturated heterocycle which may be substituted, and 4- to 10-membered unsaturated heterocycle which may be substituted.
• C 1-6 alkyl which may be substituted, C 3-10 cycloalkyl which may be substituted, C 6-14 aromatic hydrocarbon which may be substituted, 4- to 10-membered saturated heterocycle which may be substituted, and 4- to 10-membered unsaturated heterocycle which may be substituted” include halogen, hydroxyl, cyano, nitro, alkyl having 7 or more carbon atoms (e.g., C 7-15 alkyl) which may be substituted, haloalkyl which may be substituted, cycloalkyl having 11 or more carbon atoms which may be substituted (e.g., C 11-15 cycloalkyl which may be substituted), cycloalkyl-alkyl which may be substituted, aralkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, alkoxy which may be substituted, haloalkoxy which may be substituted, cycloalkoxy which may be substituted, cyclo
• R 1 represents a functional group
• the substituents mentioned above are not limited as long as they do not adversely affect the production method of the present invention.
• substituents for C 1-6 alkyl represented by R 1 are not limited as long as they do not adversely affect the production method of the present invention. Examples include halogen, C 1-6 alkoxy, acyl, C 2-7 alkoxycarbonyl, C 1-6 alkylamino, C 3-10 cycloalkyl, C 6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, 4- to 10-membered unsaturated heterocycle, and the like.
• substituents for C 3-10 cycloalkyl, C 6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, 4- to 10-membered unsaturated heterocycle represented by R 1 are not limited as long as they do not adversely affect the production method of the present invention. Examples include halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, acyl, C 2-7 alkoxycarbonyl, C 1-6 alkylamino, C 3-10 cycloalkyl, C 6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, 4- to 10-membered unsaturated heterocycle, and the like.
• substituents for amino represented by R 3 are not limited as long as they do not adversely affect the production method of the present invention. Examples include C 1-6 alkyl, C 1-6 haloalkyl, acyl, C 2-7 alkoxycarbonyl, C 1-6 alkylamino, C 3-10 cycloalkyl, 4- to 10-membered saturated heterocycle, and the like.
• the substituents for amino represented by R 3 may include protecting groups to be removed after a predetermined reaction process, as well as substituents that are not protecting groups, as long as they do not adversely affect the production method of the present invention.
• the number of substituents is typically one to three.
• halogen represented by X in the formula may be those listed above, and is preferably bromine or iodine.
• R 1 is more preferably hydrogen, C 3-7 cycloalkyl, C 6-14 aromatic hydrocarbon, or 4- to 10-membered unsaturated heterocycle.
• C 3-7 cycloalkyl group represented by R 1 in the formulae may be, for example, those listed above, and is preferably cyclopropyl.
• C 6-14 aromatic hydrocarbon represented by R 1 in the formulae may be, for example, those listed above, and is preferably phenyl.
• the "4- to 10-membered unsaturated heterocycle" represented by R 1 in the formulae may be, for example, those listed above. It is preferable to use 4- to 10-membered monocyclic or bicyclic unsaturated heterocycle having 1 to 4 atoms selected from among oxygen, nitrogen, and sulfur. It is more preferable to use monocyclic or bicyclic unsaturated heterocycle containing at least one nitrogen atom in the ring, and further containing in the ring 0 to 3 heteroatoms of the same or different types selected from oxygen, nitrogen, or sulfur. It is still more preferable to use quinolyl.
• the protecting group for the "hydroxyl protected by a protecting group” is lower alkylsilyl, lower alkyldiphenylsilyl, lower alkyl lower alkoxyphenylsilyl, or lower alkoxydiphenylsilyl.
• lower alkyl refers to C 1-6 straight or branched alkyl, unless otherwise defined. Specific examples include methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec -butyl, tert -butyl, pentyl, hexyl, and the like.
• lower alkoxy refers to alkoxy whose alkyl moiety is a lower alkyl listed above, unless otherwise defined.
• lower alkylsilyl examples include triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl, di- tert -butylmethylsilyl, and the like.
• lower alkyldiphenylsilyl examples include tert-butyldiphenylsilyl and the like.
• lower alkyl lower alkoxyphenylsilyl examples include tert -butylmethoxyphenylsilyl and the like.
• lower alkoxydiphenylsilyl examples include tert-butoxydiphenylsilyl and the like.
• tert -butyldimethylsilyl triisopropylsilyl, tert- butyldiphenylsilyl, and the like are preferable, and tert-butyldimethylsilyl and the like are most preferable.
• Alkyloxycarbonyl which may be substituted as used herein as a protecting group for amino or C 1-6 alkylamino represented by R 2 or R 2 ' is not particularly limited. Examples include alkyloxycarbonyl, whose alkyl moiety has 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms) and which may be substituted, and the like. Examples of substituents for alkyloxycarbonyl include halogen, adamantyl, trimethylsilyl, phenyl, methoxyphenyl, nitrophenyl, anthryl, fluorenyl, and the like. When substituted, alkyloxycarbonyl is substituted with, for example, one to three substituents.
• alkyloxycarbonyl which may be substituted include lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl; 1-adamantyloxycarbonyl; 2-adamantyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 2-trimethylsilylethoxycarbonyl; aralkyloxycarbonyl groups, such as benzyloxycarbonyl, 3,5-di-tert-butylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, phenethyloxycarbonyl, and 9-anthrylmethoxycarbonyl; 9-fluorenylmethoxycarbonyl; and the like.
• tert -butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, and the like are preferable, with
• C 1-6 alkylamino represented by R 2 or R 2 ' of the formulae represents mono(C 1-6 alkyl)amino. Specific examples include methylamino, ethylamino, n -propylamino, isopropylamino, n -butylamino, isobutylamino, and the like, with mono(C 1-4 alkyl)amino being preferable, and methylamino being more preferable.
• protected C 1-6 alkylamino refers to an amino group, in which one of the hydrogen atoms of the amino group is replaced by C 1-6 alkyl, and the other is replaced by alkyloxycarbonyl which may be substituted.
• protected C 1-6 alkylamino is preferably protected C 1-4 alkylamino, and more preferably protected methylamino.
• the protecting group for thiol protected by a protecting group is aralkyl, benzyloxymethyl, benzylthiomethyl, lower alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, tert- butylsulfanyl, or 3-nitro-2-pyridinesulfenyl.
• aralkyl include, but are not particularly limited to, benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl, and the like.
• lower alkoxycarbonyl examples include, but are not limited to, tert -butoxycarbonyl and the like.
• these protecting groups in particular, p-methoxybenzyl, tert -butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the like are preferable, and tert -butoxycarbonyl is most preferable.
• R 1 , R 2 , and R 2 ' may be the following:
• R 1 , R 2 , and R 2 ' may also be the following: R 1 is a functional group other than the "C 1-6 alkyl which may be substituted, C 3-10 cycloalkyl which may be substituted, C 6-14 aromatic hydrocarbon which may be substituted, 4- to 10-membered saturated heterocycle which may be substituted, and 4- to 10-membered unsaturated heterocycle which may be substituted" mentioned above; and one of R 2 or R 2 ' is hydroxyl protected by a protecting group selected from the group consisting of lower alkylsilyl, lower alkyldiphenylsilyl, lower alkyl lower alkoxyphenylsilyl, and lower alkoxydiphenylsilyl, amino or C 1-6 alkylamino protected by alkyloxycarbonyl which may be substituted, or thiol protected by a protecting group selected from the group consisting of aralkyl, benzyloxymethyl, benzylthiomethyl, lower alkoxycarbonyl, 2,2,
• R 1 , R 2 , and R 2 ' may further be the following:
• R 3 is preferably amino.
• the compound represented by Formulae (1) and (2) is preferably represented by Formulae (1) and (2) having the preferable combination of m, n, X, R 1 , R 2 , R 2 ', and R 3 , and more preferably represented by Formulae (1) and (2) having more preferable combination of m, n, X, R 1 , R 2 , R 2 ', and R 3 .
• the salts of the compounds represented by Formulae (1) and (2) refer to salts commonly used in the field of organic chemistry, and are not limited as long as they do not adversely affect the production method of the present invention. Examples include salts, such as base addition salts of the compound having a carboxyl group with a base added to the carboxyl group; and acid addition salts of the compound having an amino group or a basic heterocyclic group, with an acid added to the amino group or the basic heterocyclic group.
• base addition salts include alkali metal salts, such as sodium salts and potassium salts; alkaline earth metal salts, such as calcium salts and magnesium salts; ammonium salts; and organic amine salts, such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N , N' -dibenzylethylenediamine salts.
• alkali metal salts such as sodium salts and potassium salts
• alkaline earth metal salts such as calcium salts and magnesium salts
• ammonium salts such as sodium salts and organic amine salts, such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N , N' -dibenzylethylenediamine salts.
• acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates.
• inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates
• organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates
• sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and
• the following describes a method for producing the compound that is represented by Formula (2) and that is a starting material of the present invention.
• the method for producing the compound that is represented by Formula (2) and that is a starting material of the present invention is not limited to the following.
• the compound that is represented by Formula (2) and that is a starting material of the present invention may be produced, for example, by the following production method 1 when R 1 represents a functional group, and at least one of R 2 or R 2 ' is amino or C 1-6 alkylamino protected by alkyloxycarbonyl which may be substituted, or thiol protected by the protecting group mentioned above.
• L 1 represents a leaving group
• R 4 and R 5 represent hydrogen or a substituent for amino
• R 1 , m, n, and X are as defined above.
• R 2a or R 2a ' is amino or C 1-6 alkylamino protected by alkyloxycarbonyl which may be substituted, or thiol protected by a protecting group selected from the group consisting of aralkyl, benzyloxymethyl, benzylthiomethyl, lower alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, tert -butylsulfanyl, and 3-nitro-2-pyridinesulfenyl; and the other one of R 2a and R 2a ' is hydrogen.
• the compound represented by Formula (3) and the compound represented by Formula (4) are used to perform a Mitsunobu reaction to produce the compound represented by Formula (5).
• a Mitsunobu reaction may be performed according to a known method (e.g., the method described in Synthesis, p. 1, 1981), or a method similar to this method.
• the "substituent for amino" represented by R 4 and R 5 refers to the substituents for amino represented by R 3 mentioned above.
• R 4 and R 5 represent hydrogen, i.e., when the amino represented by R 3 is not substituted
• the compound represented by Formula (5) and ammonia or its salt are subjected to a reaction to produce the compound represented by Formula (6).
• This step is performed according to a generally known method (e.g., the method described in J. Med. Chem., 2009, 52, 5974-5989 ).
• R 4 and R 5 do not represent hydrogen, this step can be performed according to a similar method.
• R 1 is introduced to the compound represented by Formula (6) to produce the compound represented by Formula (7).
• This step can be performed according to a generally known method (e.g., Chemical Reviews, vol. 95, p. 2457, 1995 ), in the presence of a transition metal catalyst and a base in a solvent that does not adversely affect the reaction.
• a boronic acid or boronic acid ester corresponding to R 1 may be synthesized according to a generally known method.
• a halogen compound corresponding to R 1 is easily obtained, it is possible to convert the compound represented by Formula (6) into a boronic acid or boronic acid ester, and then produce the compound represented by Formula (7) by using a similar method.
• halogen is introduced into the compound (7) to produce the compound that is represented by Formula (15) and that is a starting material of the present invention.
• the halogenation may be performed by the method disclosed in WO 2006/102079 , or by a method similar thereto.
• N-bromosuccinimide may be used.
• the compound that is represented by Formula (2) and that is a starting material of the present invention may be produced, for example, by the following production method 2 when R 1 is a functional group, and at least one of R 2 or R 2 ' is hydroxyl protected by a protecting group mentioned above.
• P 1 represents a protecting group for amino
• P 2 represents a protecting group for hydroxyl
• L 1 and L 2 are leaving groups
• R 4 and R 5 are substituents for amino
• R 1 , m, n, and X are as defined above.
• the amino group may be protected by using a generally known method (e.g., the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981)), or a method similar to this method.
• a generally known method e.g., the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981)
• a method similar to this method e.g., the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981)
• the protecting group for the amino group represented by P 1 is not limited as long as it does not adversely affect the above step. Examples include trityl, p-methoxybenzyl, 2-(trimethylsilyl)ethoxymethyl, and the like.
• Step f may be performed as in step b, and step g may be performed as in step c.
• the protected amino group of the compound represented by Formula (10) is deprotected to produce the compound represented by Formula (11).
• the deprotection of amino group may be performed by a generally known method (e.g., the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981 )), or a method similar thereto.
• the compound represented by Formula (11) and the compound represented by Formula (12) or (12') are used to produce the compound represented by Formula (13) or (13') by using a generally known method (e.g., the method described in J. Med. Chem., 2009, 52, 5974-5989 ) or a method similar to this method, under basic conditions.
• the protecting group for hydroxyl represented by P 2 may be the protecting group mentioned above in relation to "hydroxyl protected by a protecting group" represented by R 2 and R 2 '.
• This step may be performed as in step d.
• R 1 of the compound that is represented by Formula (2) and that is a starting material of the present invention is hydrogen
• R 1 of the compound that is represented by Formula (2) and that is a starting material of the present invention is hydrogen
• the method of the present invention for producing a pyrrolopyrimidine ring-containing tricyclic compound represented by Formula (1) comprises the following steps.
• the method comprises a step of causing an organic borane reagent to act on a pyrrolopyrimidine derivative represented by Formula (2) or a salt thereof; and a step of performing intramolecular cyclization reaction in the presence of an alkali metal hydroxide using a zerovalent palladium catalyst.
• organic borane reagents examples include 9-BBN (9-borabicyclo[3.3.1]nonane), 9-BBN (9-borabicyclo[3.3.1]nonane)dimer, disiamylborane(bis(1,2-dimethylpropyl)borane), thexylborane((1,1,2-trimethylpropyl)borane), and the like.
• the organic borane reagent is preferably 9-BBN (9-borabicyclo[3.3.1]nonane) or 9-BBN (9-borabicyclo[3.3.1]nonane)dimer, and more preferably 9-BBN (9-borabicyclo[3.3.1]nonane).
• the amount of the organic borane reagent used is not particularly limited insofar as an alkyl borane intermediate is produced.
• the organic borane reagent may be used in an amount of 1 to 20 moles per mole of the compound represented by Formula (2); the amount of the organic borane reagent is preferably 6 to 10 moles from the viewpoint of facilitating the progress of the reaction.
• the production of alkyl borane intermediate in the system may be confirmed after the organic borane reagent is caused to act on a pyrrolopyrimidine derivative represented by Formula (2).
• LCMS spectra may be used as the confirmation method.
• alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and the like. It is preferable to use lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide. It is more preferable to use lithium hydroxide or sodium hydroxide.
• the amount of the alkali metal hydroxide used is not particularly limited insofar as the intramolecular cyclization reaction proceeds.
• the alkali metal hydroxide may be used in an amount of 1 to 100 moles, and preferably 2 to 20 moles, per mole of the compound represented by Formula (2).
• the alkali metal hydroxide may be used in the form of an aqueous alkali metal hydroxide solution.
• zerovalent palladium catalysts examples include tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium carbon(0), and the like. It is preferable to use tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0), and it is more preferable to use tetrakis(triphenylphosphine)palladium(0).
• the amount of the zerovalent palladium catalyst used is not particularly limited insofar as the intramolecular cyclization reaction proceeds, and may vary depending on the type of catalyst.
• the zerovalent palladium catalyst may be used in an amount of 0.0001 to 1 mole, and preferably 0.01 to 0.5 moles, per mole of the compound represented by Formula (2).
• a ligand may further be added, if necessary.
• ligands include triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri- tert- butylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-( N,N- dimethylamino)biphenyl, 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene, and the like.
• triphenylphosphine may be added as a ligand.
• the amount of the ligand used is not particularly limited insofar as the intramolecular cyclization reaction proceeds.
• the ligand may be used in an amount of 0.0001 to 4 moles, and preferably 0.01 to 2 moles, per mole of the compound of Formula (2).
• the combination of an organic borane reagent, an alkali metal hydroxide, and a zerovalent palladium catalyst is preferably a combination of a preferable organic borane reagent, a preferable alkali metal hydroxide, and a preferable zerovalent palladium catalyst, and more preferably a combination of a more preferable organic borane reagent, a more preferable alkali metal hydroxide, and a more preferable zerovalent palladium catalyst.
• 9-BBN (9-borabicyclo[3.3.1]nonane); at least one member selected from the group consisting of lithium hydroxide and sodium hydroxide; and tetrakis(triphenylphosphine) palladium(0).
• the combination of the compounds represented by Formulae (1) and (2) with an organic borane reagent, an alkali metal hydroxide, and a zerovalent palladium catalyst is preferably a combination of preferable compounds represented by Formulae (1) and (2) with a preferable organic borane reagent, a preferable alkali metal hydroxide, and a preferable zerovalent palladium catalyst. It is more preferable to use a combination of more preferable compounds represented by Formulae (1) and (2) with a more preferable organic borane reagent, a more preferable alkali metal hydroxide, and a more preferable zerovalent palladium catalyst.
• the solvent is not limited insofar as it does not adversely affect the reaction.
• examples thereof include hydrocarbons (e.g., benzene, toluene, and xylene), ethers (e.g., 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoryl amide), water, mixtures thereof, and the like. 1,2-Dimethoxyethane or tetrahydrofuran is preferably used.
• Tetrahydrofuran is particularly preferable from the viewpoint of stability of the organic borane reagent and the generated alkylborane intermediate.
• the amount of the solvent used is not particularly limited insofar as the reaction proceeds.
• the solvent may be used in an amount that is 1 to 300 times, and preferably 10 to 96 times, the weight of the compound of Formula (2).
• the reaction time is not particularly limited insofar as the compound of Formula (1) is obtained.
• the reaction time may be 0.1 to 100 hours, and preferably 0.5 to 24 hours.
• the reaction temperature is not particularly limited insofar as the compound of Formula (1) is ultimately obtained.
• the reaction temperature may be -20°C to the boiling temperature of the solvent, and preferably 0 to 150°C.
• a low reaction temperature tends to cause side reactions, which results in a low yield. Therefore, the temperature is preferably 61°C or higher.
• the method of the present invention may further optionally comprise additional steps.
• the compound represented by Formula (1) obtained in the present invention may further be isolated and purified.
• the isolation and purification may be performed by known isolation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
• the compound represented by Formula (1) obtained in the present invention may be subjected to other steps after or without isolation or purification.
• any of the isomers and mixtures thereof are included within the scope of the compound, unless otherwise specified.
• the compound represented by Formula (1) has optical isomers
• the optical isomer separated from a racemic mixture is also included within the scope of the compound of the present invention, unless otherwise specified.
• Each of such isomers can be obtained as a single compound by known synthesis and separation means (e.g., concentration, solvent extraction, column chromatography, and recrystallization).
• the compound represented by Formula (1) when the compound represented by Formula (1) has optical isomers, the compound represented by Formula (1) includes each of the enantiomers, as well as a mixture thereof, unless otherwise specified.
• the compound represented by Formula (1) may be a mixture of R and S enantiomers. Such a mixture may be, for example, a mixture comprising 90% or more, 95% or more, or 99% or more of R enantiomer; or a mixture comprising 90% or more, 95% or more, or 99% or more of S enantiomer.
• Methods for chiral resolution include, for example: a diastereomer method, in which a chiral resolving agent is caused to act on the compound represented by Formula (1) to form salts, and a solubility difference etc., of the obtained salts is used to obtain one of the enantiomers; a preferential crystallization method, in which one of the enantiomers is added to a supersaturated solution of a racemic mixture as a seed for crystallization; and a column chromatography method, such as HPLC using a chiral column.
• a chiral resolving agent usable in the diastereomer method may be appropriately selected from, for example, acid resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof; and basic resolving agents such as brucine, strychnine, quinine, and like alkaloid compounds, amino acid derivatives, cinchonidine, and ⁇ -methylbenzylamine.
• acid resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof
• basic resolving agents such as brucine, strychnine, quinine, and like alkaloid compounds, amino acid derivatives, cinchonidine, and ⁇ -methylbenzylamine.
• One of the enantiomers of the compound represented by Formula (1) not only by obtaining a mixture of enantiomers of the compound represented by Formula (1), followed by the above-described chiral resolution, but also by performing the above-described chiral resolution or the like of the synthetic starting material of the compound represented by Formula (1), and using one of the enantiomers thereof.
• Methods for obtaining one of the enantiomers of the compound represented by Formula (1) or one of the enantiomers of the starting material compound of the compound represented by Formula (1) include a method of preferentially obtaining one of the enantiomers by adjusting reaction conditions for a catalyst or the like in a reaction step of generating asymmetric carbon.
• the compound represented by Formula (1) obtained in the present invention may be subjected to deprotection, introduction of additional side chains, or functional group transformation, and may be used as a production intermediate of medicinal drugs and the like.
• the compound represented by the following Formula (1'), which is encompassed in Formula (1), and a salt thereof are useful as production intermediates of a quinolylpyrrolopyrimidyl condensed-ring compound, which shows antitumor activity.
• the present invention also provides a compound represented by the following Formula (1') or a salt thereof.
• R 3 is amino which may be substituted; one of R 6 or R 6 ' is amino or C 1-6 alkylamino protected by alkyloxycarbonyl which may be substituted; and the other one of R 6 or R 6 ' is hydrogen.
• R 3 , m, and n are as defined above; one of R 7 or R 7 ' is a group represented by the following Formula (17): (wherein R 8 is hydrogen or C 1-4 alkyl; R 9 , R 10 , and R 11 are identical or different and each represent hydrogen, halogen, C 1-4 alkyl, or Formula (a): -CH 2 -N(R 12 ) (R 13 ) (a), (wherein R 12 and R 13 are identical or different and each represent hydrogen or C 1-4 alkyl, or R 12 and R 13 , taken together with the nitrogen to which they are attached, may form a 4- to 6-membered heterocycloalkyl group)); and the other one of R 7 or R 7 ' is hydrogen.
• Formula (17) wherein R 8 is hydrogen or C 1-4 alkyl; R 9 , R 10 , and R 11 are identical or different and each represent hydrogen, halogen, C 1-4 alkyl, or Formula (a): -CH 2 -N(R 12 ) (
• the method for producing the quinolylpyrrolopyrimidyl condensed-ring compound represented by Formula (16) or a salt thereof from the compound represented by Formula (1') or a salt thereof may comprise the steps of:
• the deprotection of amino group may be performed by a generally known method, such as the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981), or a method similar thereto.
• hydrochloric acid sulfuric acid, methanesulfonic acid, trifluoroacetic acid, or the like may be used as a deprotection reagent.
• the reagent is preferably used in an amount of 1 to 100 moles per mole of the compound represented by Formula (1').
• Any solvents may be used in the reaction insofar as they do not adversely affect the reaction.
• Examples of usable solvents include water, methanol, ethanol, methylene chloride, chloroform, and the like, and mixtures of these solvents.
• the reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours.
• the reaction temperature is 0°C to the boiling point of the solvent.
• the thus-obtained deprotected compound may be subjected to the subsequent step B after or without isolation and purification by known isolation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
• isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
• step B (amidation step), the compound obtained in step A is amidated with an ⁇ , ⁇ -unsaturated carboxylic acid or an ⁇ , ⁇ -unsaturated acid chloride or bromide to produce the compound of Formula (16) of the present invention.
• the carboxylic acid is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compound obtained in step A, in the presence of a suitable condensation agent.
• the carboxylic acid may be a commercially available product, or may be produced according to a known method.
• the reaction solvent is not limited insofar as it does not adversely affect the reaction. Examples include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide, and the like, and mixtures of these solvents.
• the reaction temperature is generally -78 to 200°C, and preferably 0 to 50°C.
• the reaction time is generally 5 minutes to 3 days, and preferably 5 minutes to 10 hours.
• condensation agents include diphenylphosphoryl azide, N , N' -dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salts, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolinium chloride, O-(7-azabenzotriazo-1-yl)- N , N , N' , N '-tetramethylhexauronium hexafluorophosphate, and the like.
• the acid halide is used in an amount of 0.5 to 5 moles, and preferably 0.9 to 1.1 moles, per mole of the compound obtained in step A.
• the acid halide may be a commercially available product, or may be produced according to a known method.
• the reaction solvent is not limited insofar as it does not adversely affect the reaction. Examples thereof include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, acetonitrile, water, and the like, and mixtures of these solvents.
• the reaction temperature is typically -78 to 200°C, preferably 0 to 50°C.
• the reaction time is typically 5 minutes to 3 days, and preferably 5 minutes to 10 hours.
• a base can be added for the reaction.
• examples of usable bases include organic bases, such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-(N,N-dimethylamino)pyridine, potassium tert -butyrate, sodium tert -butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyl lithium; and inorganic bases, such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
• Such a base may be added in an amount of 1 to 100 moles, preferably 1 to 20 moles, and more preferably 1 to 10 moles per mole of the compound obtained in step A.
• the thus-obtained compound of Formula (16) may be isolated and purified by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
• separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
• the compound represented by Formula (16) or a salt thereof shows antitumor activity as described below.
• a preferable mode of R 3 , m, and n in the compound represented by Formula (1') is as defined above.
• Alkyloxycarbonyl which may be substituted as used herein as a protecting group for amino or C 1-6 alkylamino represented by R 6 and R 6 ' is not particularly limited. Examples include alkyloxycarbonyl, whose alkyl moiety has 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms) and which may be substituted, and the like. Examples of substituents for alkyloxycarbonyl include halogen, adamantyl, trimethylsilyl, phenyl, methoxyphenyl, nitrophenyl, anthryl, fluorenyl, and the like. When substituted, alkyloxycarbonyl is substituted with, for example, one to three substituents.
• alkyloxycarbonyl which may be substituted include lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl; 1-adamantyloxycarbonyl; 2-adamantyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 2-trimethylsilylethoxycarbonyl; aralkyloxycarbonyl groups, such as benzyloxycarbonyl, 3,5-di-tert-butylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, and 9-anthrylmethoxycarbonyl; 9-fluorenylmethoxycarbonyl; and the like.
• tert -butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, and the like are preferable, with
• protected C 1-6 alkylamino refers to an amino group, in which one of the hydrogen atoms of the amino group is replaced by C 1-6 alkyl, and the other is replaced by alkyloxycarbonyl which may be substituted.
• protected C 1-6 alkylamino is preferably protected C 1-4 alkylamino, and more preferably protected methylamino.
• Examples of preferable compounds of the present invention include the following. However, the compounds of the present invention are not limited to these examples.
• the salts of the compounds represented by Formula (1') refer to salts commonly used in the field of organic chemistry. Examples include salts exemplified above as salts of the compounds represented by Formulae (1) and (2).
• the compound represented by Formula (1') or a salt thereof may be produced by the production method of the present invention. However, the method is not limited thereto.
• any of the isomers and mixtures thereof are included within the scope of the compound represented by Formula (1'), unless otherwise specified.
• the compound represented by Formula (1') has optical isomers
• the optical isomer separated from a racemic mixture is also included within the scope of the compound of the present invention, unless otherwise specified.
• Each of such isomers can be obtained as a single compound by known synthesis and separation means (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).
• the compound represented by Formula (1') when the compound represented by Formula (1') has optical isomers, the compound represented by Formula (1') includes all of the enantiomers and mixtures thereof, unless otherwise specified.
• the compound represented by Formula (1') may be a mixture of R and S enantiomers. Such a mixture may be a mixture comprising 90% or more, 95% or more, or 99% or more of R enantiomer; or a mixture comprising 90% or more, 95% or more, or 99% or more of S enantiomer.
• Methods for chiral resolution include, for example: a diastereomer method, in which a chiral resolving agent is caused to act on the compound represented by Formula (1') to form salts, and a solubility difference etc., of the obtained salts is used to obtain one of the enantiomers; a preferential crystallization method, in which one of the enantiomers is added to a supersaturated solution of a racemic mixture as a seed for crystallization; and a column chromatography method, such as HPLC using a chiral column.
• a chiral resolving agent usable in the diastereomer method may be appropriately selected from, for example, acid resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof; and basic resolving agents such as brucine, strychnine, quinine, and like alkaloid compounds, amino acid derivatives, cinchonidine, and ⁇ -methylbenzylamine.
• acid resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid, and derivatives thereof
• basic resolving agents such as brucine, strychnine, quinine, and like alkaloid compounds, amino acid derivatives, cinchonidine, and ⁇ -methylbenzylamine.
• One of the enantiomers of the compound represented by Formula (1') not only by obtaining a mixture of enantiomers of the compound represented by Formula (1'), followed by the above-described chiral resolution, but also by performing the above-described chiral resolution or the like of the synthetic starting material of the compound represented by Formula (1'), and using one of the enantiomers thereof.
• Methods for obtaining one of the enantiomers of the compound represented by Formula (1') or one of the enantiomers of the starting material compound of the compound represented by Formula (1') include a method of preferentially obtaining one of the enantiomers by adjusting reaction conditions for a catalyst or the like in a reaction step of generating asymmetric carbon.
• reagents used in the following examples are commercially available reagents unless particularly indicated otherwise.
• silica gel column chromatography the following columns were used: Purif-Pack (registered trademark) SI produced by Moritex Corporation (Shoko Scientific Co., Ltd.), KP-Sil (registered trademark) Silica Prepacked Column produced by Biotage, and HP-Sil (registered trademark) Silica Prepacked Column produced by Biotage.
• Purif-Pack registered trademark
• KP-Sil registered trademark
• Silica Prepacked Column produced by Biotage
• HP-Sil registered trademark
• Silica Prepacked Column produced by Biotage.
• AL400 400 MHz; Nihon Denshi (JEOL Ltd.)
• Mercury 400 400 MHz; Varian
• the measurement was carried out using tetramethylsilane as an internal standard when tetramethylsilane was contained in a deuterated solvent; otherwise, an NMR solvent was used as an internal standard.
• the value ⁇ is indicated in ppm.
• the microwave reaction was carried out using an initiator produced by Biotage.
• N -bromosuccinimide (3.63 g) was added to a solution of the ( S )- tert -butyl (1-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (7.98 g) obtained in Step 3 in DMF (64 ml) at -15°C, and the mixture was stirred at - 15°C for one hour. A 10% aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction mixture, and then the mixture was stirred at room temperature for 10 minutes.
• the organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice.
• the obtained organic layer was washed with a saturated sodium chloride solution twice, and dried over anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol), thereby giving 6.30 g of the title compound as a pale brown solid.
• the mixture was degassed under reduced pressure for 1 minute, and nitrogen gas was introduced thereto, followed by heating with stirring at 100°C for 1.5 hours using a microwave reactor.
• Cyclopropylboronic acid 0.30 g
• tricyclohexylphosphine 29.2 mg
• tetrakis(triphenylphosphine)palladium(0) 49.2 mg
• the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate, followed by drying of the extract over anhydrous sodium sulfate.
• a 2M aqueous sodium carbonate solution (38 ml) was added to a solution of the 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15.0 g) obtained in Step 2, 3-quinolineboronic acid (8.6 g), and tetrakis(triphenylphosphine)palladium(0) (2.2 g) in DME (270 ml), and the mixture was stirred at 90°C in a nitrogen atmosphere for 6 hours. The reaction mixture was cooled, and then water (300 ml) was added thereto, followed by filtration of the obtained precipitate.
• the obtained precipitate was filtered off, washed with water, and dried under reduced pressure, followed by purification of the obtained residue by silica gel column chromatography (developing solvent: methanol/ethyl acetate), thereby giving 1.31 g of the title compound as a pale yellow solid.
• a biotinylated amino acid biotin-EEPLYWSFPAKKK
• a series reagent of LabChip registered trademark
• LabChip registered trademark
• EGFR T790M/L858R
• T790M/L858R a purified recombinant human EGFR (T790M/L858R) protein of Carna Biosciences, Inc. was purchased.
• the measuring procedure is as follows.
• the compounds prepared in Reference Examples 13 to 16 were individually diluted with dimethyl sulfoxide (DMSO) in stages. Subsequently, the EGFR (T790M/L858R) protein, the substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 1 ⁇ M), and each DMSO solution of the compound (final concentration of DMSO: 2.5%) were added to a buffer solution for the kinase reaction (Carna Biosciences, Inc.). The mixtures were incubated at 25°C for 120 minutes to carry out a kinase reaction.
• DMSO dimethyl sulfoxide
• EDTA was then added thereto such that the final concentration became 24 mM, thereby terminating the reaction.
• a detection liquid containing europium (Eu)-labeling anti-phosphorylated tyrosine antibody PT66 (PerkinElmer, Inc.) and SureLight APC-SA (PerkinElmer, Inc.) was added to each of the reaction mixtures, and the mixtures were allowed to stand at room temperature for 2 hours or more.
• the amount of fluorescence at the time of irradiation of excitation light having a wavelength of 337 nm was measured at dual wavelengths of 620 nm and 665 nm by PHERAstar FS (BMG LABTECH). The amount of phosphorylation was determined from the ratio of the fluorescence amounts at the dual wavelengths, and the IC 50 value (nM), which is a compound concentration at which phosphorylation can be inhibited by 50%, was determined.
• EGFR d746-750/T790M
• a purified recombinant human EGFR (d746-750/T790M) protein of Carna Biosciences, Inc. was purchased.
• the final concentration of ATP was 1.5 ⁇ M.
• the IC 50 value was determined using the same materials and the same measuring method used in the measurement of EGFR (T790M/L858R) kinase inhibitory activity.
• EGFR a purified recombinant human EGFR (L858R) protein of Carna Biosciences, Inc. was purchased. The final concentration of ATP was 4 ⁇ M.
• IC 50 value nM was determined.
• EGFR a purified recombinant human EGFR (d746-750) protein of Carna Biosciences, Inc. was purchased. The final concentration of ATP was 5 ⁇ M. The incubation for a kinase reaction was carried out for 90 minutes. In addition, using the same materials and the same measuring method used in the measurement of EGFR (T790M/L858R) kinase inhibitory activity, the IC 50 value (nM) was determined.
• EGFR human EGFR (WT) intracytoplasmic domain having a FLAG tag fused to its N-terminus was expressed in the insect cell Sf9 using a baculovirus expression system, and purified using anti-FLAG antibody agarose (Sigma-Aldrich Co. LLC) for use.
• the final concentration of the substrate peptide was 500 nM, and the final concentration of ATP was 4.7 ⁇ M.
• the IC 50 value was determined using the same materials and the same measuring method used in the measurement of EGFR (T790M/L858R) kinase inhibitory activity.
• the compounds prepared in Reference Examples 13 to 16 exhibited potent inhibitory activity against not only EGFR (L858R) and EGFR (d746-750), but also EGFR (T790M/L858R) and EGFR (d746-750/T790M). In contrast, the compounds exhibited weak inhibitory activity against EGFR (WT).
• Tetrakis(triphenylphosphine)palladium(0) (0.136 g) was added thereto in a nitrogen atmosphere, and the mixture was stirred at 64°C for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution was added thereto. At this stage, the generated insoluble substances were removed by filtration, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, thereby giving a crude product.
• Example 2 The same procedure as in Example 1 was repeated using a 4N aqueous lithium hydroxide solution (1.8 ml) in place of the aqueous sodium hydroxide solution in Example 1, thereby giving 224 mg of ( S )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 88%).
• Example 2 The same procedure as in Example 1 was repeated using a 4N aqueous potassium hydroxide solution (1.8 ml) in place of the aqueous sodium hydroxide solution in Example 1, thereby giving 198 mg of ( S )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 78%).
• Example 2 The same procedure as in Example 1 was repeated using a 4N aqueous cesium hydroxide solution (1.8 ml) in place of the aqueous sodium hydroxide solution in Example 1, thereby giving 202 mg of ( S )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 80%).
• Example 2 The same procedure as in Example 1 was repeated using tris(dibenzylideneacetone)dipalladium(0) (34 mg) and triphenylphosphine (39 mg) in place of the tetrakis(triphenylphosphine)palladium(0) in Example 1, thereby giving 194 mg of ( S )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 76%).
• Example 2 The same procedure as in Example 1 was repeated using 6.70 g of the ( R )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Reference Example 2 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 4.76 g of ( R )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 84%).
• Example 2 The same procedure as in Example 1 was repeated using 0.9 g of the ( R )- tert -butyl (1-(4-amino-6-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Reference Example 4 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 0.54 g of (R)-tert- butyl (4-amino-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate as a pale yellow solid (yield: 76%).
• Example 2 The same procedure as in Example 1 was repeated using 270.0 mg of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Reference Example 6 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 112.7 mg of the title compound as a pale yellow solid (yield: 51%).
• Example 2 The same procedure as in Example 1 was repeated using 1.57 g of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Reference Example 7 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 922 mg of the title compound as a pale yellow solid (yield: 71%).
• Example 2 The same procedure as in Example 1 was repeated using 2.0 g of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-4-en-2-yl)carbamate obtained in Reference Example 8 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 1.56 g of the title compound as a pale yellow solid (yield: 92%).
• Example 2 The same procedure as in Example 1 was repeated using 690 mg of the ( R )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-4-en-2-yl)carbamate obtained in Reference Example 9 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 429 mg of the title compound as a yellow solid (yield: 73%).
• Example 2 The same procedure as in Example 1 was repeated using 994 mg of the ( R )- tert -butyl (5-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-1-en-3-yl)carbamate obtained in Reference Example 10 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 439 mg of the title compound as a yellow solid (yield: 52%).
• Example 2 The same procedure as in Example 1 was repeated using 800 mg of the ( R )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)(methyl)carbamate obtained in Reference Example 12 in place of the ( S )- tert -butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate in Example 1, thereby giving 432 mg of ( R )- tert -butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)(methyl)carbamate as a pale brown solid (yield: 64
• Example 1 The compound of Example 1 was produced in accordance with the procedure disclosed in International Publication WO 2006/102079 (pamphlet). Specifically, the same procedure as in Example 1 was repeated using 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (32 mg) in place of the tetrakis(triphenylphosphine)palladium(O) in Example 1, thereby giving 21 mg of the compound of Example 1 as a pale yellow solid (yield: 25%).
• Example 1 The compound of Example 1 was produced in accordance with the procedure disclosed in Synthesis (2010, No. 127, 2092-2100 ). Specifically, the same procedure as in Example 1 was repeated using cesium carbonate (2.3 g) and water (1.8 ml) in place of the aqueous sodium hydroxide solution in Example 1, thereby giving 88 mg of the compound of Example 1 as a pale yellow solid (yield: 35%).

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